The first case of AIDS patient was discovered in the United States in 1981. It was until in 1983 that the AIDS virus (HIV) is isolated and identified by scientists, revealing that HIV composed of 9749 nucleotides only is categorized into the Lentivirinae in Retroviridae. At present, the replication cycle of HIV virus has been made generally clear. According to relevant research findings, the reproduction process of the HIV virus can be divided into the following steps: the viral adsorption, invasion and uncoating, the reverse transcription, the integration of virus as well as the synthesis, the assembly, the release and the maturing of viral RNA and protein. Each of these steps can be used as a target for screening the Anti-HIV drugs, and the protein synthesis and the viral genome DNA replication are the most critical steps. At present, the screening of anti-HIV drugs is focused on finding the inhibitors for these specific enzymes, including the reverse transcriptase (RT) inhibitors, the protein synthesis inhibitors and the reverse transcriptase initiation inhibitors. HIV-reverse transcriptase is a multifunctional enzyme, which also has the activities of RNA dependent DNA polymerase, DNA dependent DNA polymerase and RNase H. Initially, DNA chain (−) synthesis of HIV is processed with the virus genome RNA acting as a template and the host cell RNA as a primer, and then the synthesis of DNA chain (+) is completed in the same way. After the completion of the reverse transcription, all the genetic information carried by HIV is transformed from single-stranded RNA into double-stranded mDNA. Reverse transcriptase inhibitors can prevent the extension of mDNA and interfere with the HIV reverse transcription process, and thus become the drugs for the chemotherapy of AIDS. According to different mechanisms of the inhibitors, these drugs could be divided into two categories: 1) the nucleoside reverse transcriptase inhibitors which realize anti-HIV actions by being inserted into the viral DNA to promote the viral DNA to become defective DNA, resulting in the invalid duplication after integration of HIV with host cell during HIV DNA reverse transcription, and the available drugs include Zidovudine (AZT), Didanosine (ddI), Zalcitabine (ddC), Stavudine (d4T), Lamivudine (3TC), Abacavir; 2) non-nucleoside reverse transcriptase inhibitors, and mechanisms thereof are to prevent HIV RNA from being directly connected to the RT and thus being encoded into DNA. The available drugs include Nevirapine, Delavirdine and Efavirenz.
Zidovudine, the first commercial anti-HIV drug that was put into market in 1987, is a nucleoside reverse transcriptase inhibitor. This drug can alleviate the symptoms and prolong the lives of the patients, although it has much toxicity and failed to cure any patient. Later, several anti-HIV nucleoside analogue agents have also become available in the market. Therefore, nucleoside analogues are considered as an important class of compounds with anti-HIV activity. However, these drugs have some shortcomings at present. On the one hand, their effect is limited; on the other hand, severe toxic and side effects and drug resistance will be generated in a long-term administration. Accordingly, the synthesis of new nucleoside analogues is still an important trend in the research. In order to find more effective nucleoside anti-viral agents, diversified chemical modifications have been made for the nucleosides, including the fluorine-containing nucleoside analogues (Clark, J. PCT Patent Appl., WO 2005003174; Ismaili, H. M. A. PCT Patent Appl., WO 0160315A22001). Relevant studies have shown that these compounds have anti-viral activity at different levels, and are a new type of compounds with anti-viral activities. However, in the currently available literatures, it is not found any relevant report on the synthesis of 2′-fluoro-4′-substituted-D- and L-nucleoside analogues of the present invention as well as on their applications in the preparation of anti-HIV, anti-HBV and anti-HCV drugs.